Chlamydia (C.) pneumoniae is a major agent of community-acquired upper and lower respiratory infection and pneumonia. Increasing evidence suggests that C. pneumoniae infection plays an integral role in atherosclerotic coronary heart disease in developed countries, making C. pneumoniae a major public health concern. This clearly merits an effort to develop a vaccine against C. pneumoniae for prevention or treatment of respiratory disease, and possibly coronary heart disease and atherosclerosis. Using our new genetic immunization technologies, we are able to deconvolute the genomes of pathogens into the best vaccine candidates, and have recently validated this in a mouse model of C. psittaci infection in which we found 10 protective genes that also protect the original host animal. Perusing the complete genome sequence of C. pneumoniae, we propose as first step towards a C. pneumoniae vaccine to i) examine the C. pneumoniae homologs of the protective C. psittaci genes for protective efficacy in a mouse model of C. pneumoniae respiratory infection; ii) conduct a C. pneumoniae genome-wide search for the best antigens mediating prophylactic immunity against respiratory infection; and iii) perform experiments to understand the mechanisms for the success of such immunological intervention. We propose the following specific aims: 1) Test the C. pneumoniae homologs of the 10 protective C. psittaci genes in a mouse prophylactic respiratory model of C. pneumoniae infection. 2) Screen all approximately 1,000 C. pneumoniae genes for their protective efficacy in the mouse prophylactic model. 3) To understand the spectrum of possible responses in an outbred human population, dissect the immunological mechanisms of disease protection mediated by the C. pneumoniae vaccine candidate proteins in respiratory disease models using several inbred mouse strains.